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Transcriptional repression by Polycomb Repressive Complex 2

Polycomb 抑制复合物 2 的转录抑制

基本信息

批准号：
10390294
负责人：
Zachary Lewis
金额：
$ 34.93万
依托单位：
UNIVERSITY OF GEORGIA
依托单位国家：
美国
项目类别：
财政年份：
2019
资助国家：
美国
起止时间：
2019-05-01 至 2025-04-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10390294
关键词：
Address Animals Architecture Area Bioinformatics Biological Models Cells Chromatin Chromatin Remodeling Factor Chromatin Structure Complex Data Data Set Defect Deposition Development Diagnosis Environment Enzymes Epigenetic Process Eukaryota Fission Yeast Fungi Model Future Gene Deletion Gene Expression Regulation Genes Genetic Genetic Diseases Genetic Transcription Genome Genomic approach Genomics Goals HDAC1 gene Heterochromatin Histone Acetylation Histone Deacetylase Histone H3 Histones Human Human Biology ISWI Knowledge Lysine Maintenance Malignant Neoplasms Mediating Memory Methylation Methyltransferase Molecular Molecular Biology Multienzyme Complexes Mutate Mutation Neurospora Neurospora crassa Nucleosomes Organism Other Genetics Outcome Plants Play Polycomb Proteins Proteomics Regulation Repression Research Role Saccharomyces cerevisiae Site System Testing Translating Weaver Syndrome Work X Inactivation Yeast Model System Yeasts base cancer genetics cancer type chromatin modification chromatin remodeling deletion library fungus gene regulatory network gene repression genetic regulatory protein genetic resource histone methylation histone methyltransferase human disease improved in vivo insight link protein mutant network models novel prevent stem cell biology stem cells tool transcriptome sequencing

项目摘要

Project Summary The long-term goals of this project are to understand assembly of repressed chromatin states and to elucidate mechanisms of gene repression in these specialized chromatin environments. Polycomb Group (PcG) proteins interact to form enzyme complexes that modify chromatin and assemble repressed chromatin states in animals, plants, and most fungi. Polycomb Repressive Complex 2 (PRC2) is a highly conserved histone lysine-27 methyltransferase complex that is essential for multicellular development and plays key roles in maintenance of stem cell identify, X-chromosome inactivation, and gene regulation. Mutations that alter PRC2 function are responsible for human Weaver syndrome and multiple cancers. Despite its importance, we lack a clear understanding of the mechanisms that control PRC2 and repress transcription of PRC2 target genes. Preliminary studies with the model fungus Neurospora crassa have begun to address these critical gaps in knowledge. Neurospora is a powerful experimental system that shares key features with higher eukaryotes. Namely, components of PRC2 are structurally and functionally conserved, while they are lacking in both major yeasts, Saccharomyces cerevisiae and Schizosaccharomyces pombe. A targeted RNA-sequencing screen of over 400 N. crassa gene deletion strains that lack known or predicted chromatin-associated or chromatin regulatory proteins uncovered new genes required for PcG repression and are beginning to yield mechanistic insights into their functions. Application of genetic, molecular, proteomic, and genomic approaches will capitalize on these novel findings, and bioinformatic analyses will interrogate this unique RNA-seq data set to: 1) determine how a conserved ATP-dependent chromatin remodeling enzyme controls PRC2 and gene repression at PcG-repressed domains, 2) define mechanisms by which constitutive heterochromatin components regulate PRC2, and 3) define a comprehensive PcG chromatin network in a simple model system. Successful completion of the proposed aims will uncover general principles and mechanisms governing assembly and function of PcG-repressed chromatin domains. Because the first two newly identified components of PcG-mediated silencing are conserved, findings from the proposed studies will serve as a framework for future studies in higher eukaryotes, including humans. In addition, because PcG proteins are linked to cancer and other genetic diseases, understanding the regulation and function of these key chromatin regulators will ultimately improve diagnosis and treatment of human disease.

项目总结